Project Summary The United States is in the midst of an opioid overdose crisis. According to the CDC, there were more than 33,000 opioid overdose deaths in 2015 alone. The number of opioid overdose deaths has more than quadrupled since 1999, with much of this increase attributable to the rise in prescription opioid use. The mechanism of death in opioid overdose is primarily through opioid-induced respiratory arrest, defined as the centrally mediated reduction in ventilatory drive after opioid use. Naloxone, an opioid receptor antagonist that temporarily reverses this process, is the first line medication for treatment of opioid overdose, and there have been substantial efforts to reduce overdose deaths in the community by distributing naloxone rescue kits to individuals who are likely to witness opioid overdoses. These efforts have shown significant promise. However, many opioid overdose deaths that occur are either unwitnessed or naloxone is not immediately available. Additional lives could be saved by technologies that can both recognize and treat opioid overdose safely and automatically, in the absence of a bystander. The ideal technology would be safe, reliable and self- contained. Moreover, such a device would require no day-to-day maintenance (e.g. replacing of expired drug, placing of sensors), which is particularly important in a target population known to have poor compliance with treatments. Our proposal will validate a new implantable device-based approach for rescuing opioid overdose by automatically sensing and reversing the opioid-induced respiratory arrest in order to keep the patient stable until definitive treatment with naloxone can be provided. This system would be targeted towards those individuals at the highest risk for opioid overdose - those with a history of overdose, poor response to treatment, using high opioid doses, concomitant sedative-hypnotic and alcohol use, and mental disorders Coridea has previously developed an approach that uses the body's natural ability to control respiration by stimulation of the phrenic nerve. The system is a fully implantable pacemaker-like device that is currently used for the treatment of central sleep apnea in heart failure, and has been shown to be safe and effective for this purpose. It consists of a transvenous pacing lead and an implantable pacemaker-like pulse generator. It can sense specific phases/patterns of respiration and then stimulate the phrenic nerve to break the intermittent pattern of sleep disordered breathing that is characteristic of central sleep apnea in heart failure. However, this device has never been tested in the context of prolonged respiratory depression/arrest, which is characteristic of opioid overdose. The ability to fully support respiration has been previously shown using a surgically implanted phrenic nerve cuff, but not with a less invasive, transvenous design. Another novel aspect proposed in this grant is the design and development of a software algorithm to automatically detect and respond to critical respiratory depression and arrest. Our eventual clinical device will be placed via a simple 30-60-minute procedure, very similar to the currently clinically-used cardiac pacemakers or neurostimulators for pain, in the catheterization laboratory under conscious sedation and local anesthesia with patients able to go home the same day. This project will be completed in sequential stages. As deliverables for the Phase I SBIR, we will demonstrate the proof of concept by determining and optimizing the parameters of unilateral transvenous phrenic nerve stimulation required to generate a physiological pattern of respiration sufficient to stabilize gas exchange while maintaining airway patency and maintain blood oxygenation levels in an animal model of opioid-induced respiratory arrest. In parallel, we will also validate a method an index for detecting inadequate respiration using transthoracic impedance. Using the results obtained in the Phase I proof of concept studies, the future Phase II SBIR deliverables will include design and development of a software algorithm to combine automatic detection and treatment of respiratory depression/arrest. The detection algorithm will be optimized for energy efficiency to enable incorporation into a small implantable pulse generator. Following the completion of Phase II, we will seek to fund feasibility clinical trial using a combination of venture and/or industry funding, potentially also as matching funds for a Phase IIb SBIR submission. Ultimately, a fully implantable, clinically usable system will be developed that incorporates the ability to automatically call 911 and provide GPS coordinates to responders to locate the overdosed patient.